Lymphatic filariasis is caused by the parasitic nematodes Wuchereria bancrofti, and Brugia malayi which infect over 120 million people worldwide. Individuals harboring adult worms are typically asymptomatic, but patients exhibiting clinical manifestations of the disease like lymphedema are usually antigen-negative. Even though infected individuals appear asymptomatic, they exhibit subclinical manifestations such as lymphangiectasia or lymphatic vessel (LV) dilation. Lymphangiectasia is not restricted to the site of the worm nest but is seen along the length of the infected vessel suggesting a soluble product secreted by the worm could be responsible for the lymphatic pathology. Therefore, it is hypothesized that the worm excretory-secretory (ES) products are activating the lymphatic endothelial cells (LEC) lining the infected vessels. Initial studies characterized ES products and catalogued the ES protein constituents by mass spectrometry. Given the intimate interaction between the parasite and LECs, the ability of the ES products to directly activate LECs was analyzed, but there was a lack of evidence for the direct activation of LECs by ES products. Consequently, it was hypothesized that ES products indirectly activated LECs through an accessory cell type. Peripheral blood mononuclear cells (PBMC) from nave volunteers were exposed to worm ES products. ES products induced PBMCs from healthy volunteers to produce elevated levels of lymphangiogenic molecules such as IL-8, IL-6 and VEGF-A. CD14-positive monocytes were the primary producers of lymphangiogenic molecules in response to ES products. In addition, these lymphangiogenic mediators can induce LEC tubule formation in vitro and in vivo. Individuals from filarial-endemic regions of Haiti including individuals with active infection, lymphedema and endemic normal (EN) controls were also analyzed for the production of lymphangiogenic molecules in response to filarial ES products. All groups produced elevated levels of lymphangiogenic molecules in response to worm ES products and microfilaremic individuals exhibited a higher frequency of monocytes producing lymphangiogenic mediators compared to ENs. Taken together, these data suggest filarial ES products activate circulating cells to produce lymphangiogenic mediators that may contribute to the lymphangiectasia seen in infected individuals and thus the development of lymphedema.